European Respiratory Journal最新文献

Background: Large-scale genetic and epigenetic studies have identified numerous genes linked to lung function. However, proteomics, which can offer more direct insights into pathophysiologic processes, remains underexplored. We aimed to identify circulating proteins related to lung function.

Methods: In 20 823 adults (71% European, 15% African, and 15% Asian ancestries) across five cohorts we investigated spirometry parameters (FEV₁, FVC, and FEV₁/FVC) in relation to abundance in circulation of 4693 proteins assessed using the SOMAScan™ platform. Study-level associations were determined using robust linear regression, adjusting for confounders including age, sex, height, weight, and smoking. Results were then meta-analysed using inverse-variance weighting.

Results: In this multi-ancestry population, 1055 proteins were significantly associated with a lung function trait after Bonferroni correction (p<1×10^-5). The 473 enriched pathways identified include those involving inflammation and organismal injury. Protein-protein networks indicate potential orchestrators of lung function, including STAT3 and EGFR. Associations with 411 proteins were validated in the UK Biobank using the Olink 3K platform (560 overlapping proteins). 179 proteins identified were related to COPD in our data. While most associated proteins are likely biomarkers of impaired lung function, Mendelian randomisation provides preliminary evidence suggesting potential causality for 34 proteins. Our findings include known biomarkers of lung diseases including COPD. Notably, 89% of associated proteins have not been previously implicated in lung function.

Conclusion: This comprehensive investigation identified novel protein-lung function associations that could improve understanding of lung disease pathogenesis, aid in the discovery of circulating biomarkers and accelerate development of new management strategies for respiratory conditions.

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disorder with an estimated prevalence of 1/5000 to 1/7000. Pathogenic variants in three genes, endoglin (ENG), activin receptor-like kinase 1 (ACVRL1), and Mothers against decapentaplegic homolog 4 SMAD4, all part of the transforming growth factor-beta (TGF-β) signaling pathway, account for over 90% of HHT cases. Clinically, HHT is characterised by recurrent epistaxis, gastrointestinal bleeding from mucocutaneous telangiectasias, and visceral arteriovenous malformations (AVMs), most commonly affecting the lungs, liver, and brain. Pulmonary hypertension (PH) is a recognised but heterogeneous complication of HHT, with reported prevalence ranging widely from 1.5% to 45%, depending on diagnostic methods and study populations. PH associated with HHT can result from distinct, and sometimes overlapping, pathophysiological mechanisms, including, among others, high cardiac output resulting from AVMs, isolated or associated with left heart disease and precapillary PH usually consistent with pulmonary arterial hypertension (PAH). Accurate hemodynamic classification by right heart catheterisation is essential to determine the predominant mechanism and guide appropriate therapeutic strategies. These may include embolisation or other management of AVMs, assessment for hepatic transplantation, administration of anti-angiogenic therapies such as anti-VEGF agents or the use of PAH-approved drugs in selected patients with precapillary involvement. Given the complexity of PH associated with HHT, optimal management requires a multidisciplinary approach within specialised centers experienced in both diseases. This review aims to provide a comprehensive overview of genetics, clinical phenotypes, diagnostic and therapeutic challenges in PH associated with HHT.

Background: Intrapleural enzyme therapy (IET) is widely used for pleural infections, including complicated parapneumonic effusions (CPPE) and empyema; however, the role of saline lavage alone or in combination with IET remains uncertain.

Methods: The SCOPE trial was a two-center, prospective, randomised superiority study designed to determine whether saline lavage alone or combined with IET was superior to IET alone in adults with pleural infection. Patients were randomised in a 1:1:1 ratio to saline lavage alone, saline lavage plus IET (urokinase and DNase), or IET alone. Patients and outcome assessors were blinded to the treatment allocation. The primary endpoint was the duration of pleural drainage. Secondary endpoints included radiographic resolution, need for additional interventions, length of hospital stay, mortality, and adverse events.

Results: Eighty-nine patients were analysed (saline, n=30; saline+IET, n=30; IET, n=29). Baseline characteristics were broadly similar across the groups. The median drainage duration was longer with saline lavage alone (4.0 days [IQR 3.0-6.75]) than with IET alone (3.0 days [2.0-4.0], p=0.01) or saline+IET (3.0 days [3.0-3.75], p=0.01). No significant difference was observed between the two IET-containing regimens (p=0.24). Secondary outcomes showed no clear advantage for saline lavage alone or in combination with IET.

Conclusions: In pleural infection, saline lavage alone results in a longer drainage duration than IET. In this small superiority trial, adding saline lavage to IET did not demonstrate a clinically meaningful advantage over IET alone.

Obesity affects more than 650 million adults worldwide, with prevalence continuing to rise across all age groups and continents. This trend has important implications for asthma: individuals with obesity have a 30-50% higher risk of developing asthma, and obesity is highly prevalent among people with established disease. Mean Body Mass Index (BMI) in clinical trials and registries of adults with asthma consistently ranges from 28-30 kg·m^-2, with up to 70% of patients being overweight or obese. These numbers highlight obesity as one of the most common comorbidities in asthma, consistently associated with poorer asthma control and a higher risk of exacerbations. Although obesity-associated asthma is often described as Type-2 (T2)-low phenotype, it is increasingly recognized as a heterogeneous condition not restricted to a single phenotype. Excess adiposity influences asthma through multiple mechanisms, including dysregulated adipokine signaling, impaired ILC2-eosinophil-macrophage crosstalk in adipose tissue, systemic low-grade inflammation, metabolic dysfunction, and mechanical effects on lung volumes. This diversity complicates diagnosis, endotyping, and treatment stratification. Obesity should therefore be considered a treatable trait in asthma. Weight reduction - through lifestyle interventions, pharmacotherapy, or bariatric surgery - improves symptoms, lung function, and exacerbation risk across both T2-high and T2-low asthma. Importantly, patients with obesity experience similar reductions in exacerbations with anti-T2 biologics as their lean counterparts, though improvements in symptoms and lung function are variable. Future research should prioritize randomized, placebo-controlled trials evaluating GLP-1 and dual GLP-1/GIP-agonist therapies specifically in patients with asthma and obesity, and elucidate how obesity modifies inflammatory endotypes and treatment responses.

Background: Eosinophilic inflammation is a feature of allergic asthma, with eosinophil depletion shown to alleviate symptoms. Elevated levels of eosinophil extracellular traps (EETs) in bronchoalveolar lavage fluid (BALF) correlate with asthma severity. Sj16 is a protein from Schistosoma japonicum with known immunoregulatory properties. Exosomes, with their protective phospholipid bilayer, serve as efficient drug carriers.

Methods: We extracted exosomes secreted by Escherichia coli Nissle 1917 engineered to express Sj16 (EcN-Sj16-Exo), and sought to investigate the role of EcN-Sj16-Exo on asthma. In ovalbumin (OVA)-induced experimental asthma model in mice, EET levels were elevated. The experimental asthma model was treated with EcN-Sj16-Exo. EET formation was assessed using immunofluorescence and scanning electron microscopy. Lung function, airway remodeling, and inflammatory were evaluated. Wiskott-Aldrich syndrome-like (WASL) knockout mice and recombinant adeno-associated virus (rAAV)-expressing Neural Wiskott-Aldrich syndrome protein (N-WASP) were used to investigate the potential mechanisms of EcN-Sj16-Exo.

Results: EET formation was increased in sputum and BALF from asthma patients. We demonstrate that Sj16 inhibits EET formation in vitro and localizes primarily in exosomes when secreted by EcN-Sj16. In the experimental asthma model, EcN-Sj16-Exo significantly reduced EET formation. Moreover, EcN-Sj16-Exo significantly attenuated airway hyperreactivity (AHR) and airway remodeling, as evidenced by reduced lung resistance (R_L), improved dynamic compliance (C_dyn), and diminished inflammatory cell infiltration, fibrosis, and mucus hypersecretion. Furthermore, EcN-Sj16-Exo decreased eosinophil and neutrophil counts, IgE, and type 2 cytokines levels in BALF while increasing Treg cells in the spleen. Mechanistically, EcN-Sj16-Exo inhibited EET formation by upregulating N-WASP. WASL knockout mice and AAV6-WASL-mediated N-WASP expression confirmed that EcN-Sj16-Exo alleviates experimental asthma by upregulating N-WASP to inhibit EET formation.

Conclusion: Our findings suggest that EcN-Sj16-Exo represents a promising therapeutic approach in asthma, highlighting the potential of targeting EETs and N-WASP in asthma therapy.

Rationale: Cystic fibrosis is caused by variants in the CF transmembrane conductance regulator (CFTR), leading to defective chloride ion transport and multi-organ dysfunction. CFTR modulators substantially improve chloride ion transport and disease severity, but responses vary, which may in part be due to variation in drug concentrations.

Objectives: This study aimed to evaluate modulator concentrations among people with CF and the potential impact of cytochrome P450 (CYP) 3A5 genotypes on sweat chloride.

Methods: This multicenter study enrolled 97 children and adult participants established on elexacaftor/tezacaftor/ivacaftor (ETI) therapy. ETI drug concentrations were quantified and CYP3A5 genotypes were determined. Relationship between drug concentrations, genotype, and sweat chloride response were investigated using correlation and multivariable regression models to examine associations between drug levels and sweat chloride.

Measurements and main results: Plasma concentrations of elexacaftor, tezacaftor and ivacaftor were highly variable. Analyses revealed that CYP3A5 genotype status had no significant effect on drug concentrations. Association analysis demonstrated an association of sweat chloride with drug concentrations including after adjusting for pre-modulator sweat chloride, age, race, BMI, and sex, showing that lower drug concentrations are associated with worse outcomes in sweat chloride.

Conclusion: This study provides evidence that lower drug concentration are associated with worse sweat chloride levels and may be a potential indicator of therapeutic effectiveness, especially for people with high sweat chloride despite treatment. The influence of drug variability underscores the need for personalised dosing strategies to improve CF treatment outcome, although well-known CYP3A5 genotypes are unlikely to be helpful.

Recent studies using computed tomography (CT) have uncovered a high prevalence of airway mucus plugs in patients with asthma and COPD. These mucus plugs persist in the same airways for years and often occur in patients without symptoms of cough and sputum production. Mucus plugs associate strongly with measures of airflow obstruction and disease morbidity in both asthma and COPD, and they occur and persist despite treatment with high doses of inhaled and oral corticosteroids. Thus, airway mucus plugs have emerged as an underappreciated airway pathology in asthma and COPD and a cause of persistent airflow obstruction and disease morbidity that can be specifically targeted for treatment. This narrative review covers the pathobiology of mucus plugs in asthma and COPD with three areas of emphasis: (i) Prevalence and clinical features; (ii) Mechanisms of formation and persistence; (iii) Current and emerging treatments.